Packaging system for oxygen-sensitive drugs

ABSTRACT

Described herein are pharmaceutical packaging systems which prevent oxidative degradation of morphine, hydromorphone, promethazine and other oxygen-sensitive drugs, such systems including a syringe with an oxygen permeable tip cap, a hermetically sealed oxygen barrier blister packaging with very low permeability to oxygen and comprises ethylene vinyl, and an oxygen absorber.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Application Ser. No.61/785,158, filed Mar. 14, 2013, which is hereby incorporated byreference in its entirety.

BACKGROUND OF THE INVENTION

Oxygen sensitivity in drugs and their formulations is a large concern inpharmaceutical development. Often, the oxygen sensitive drug orformulation requires additional excipients, packaging and/ormanufacturing steps for stability enhancement and degradationprevention. Chemical approaches, such as pH control, addition of anantioxidant, and control of components are usually considered first as ameans of enhancing stability of oxygen-sensitive solutions. A downsideof chemical approaches is added complexity to the formulation andadditional research needed for identity, compatibility and toxicity ofsuitable excipients. Nitrogen gassing of a solution and nitrogenblanketing of a container during and/or after filling of a drug is alsocommonly used in the pharmaceutical industry. However, the efficiency ofthis process is limited and leads to a residual oxygen level of a fewpercent. With this standard manufacturing and filling process, the shelflife of oxygen sensitive products is generally reduced to typicallyaround six months as compared to drugs that are not sensitive to oxygen.

SUMMARY OF THE INVENTION

Provided herein are pharmaceutical packaging system for an injectableoxygen-sensitive drug. In one aspect, the pharmaceutical packagingsystem comprises a primary packaging container comprising anoxygen-sensitive drug, wherein the primary packaging container has anoxygen permeable component and wherein the primary packaging containeris packaged under inert conditions, a hermetically sealed secondarypackaging which envelops the primary packaging container, wherein thesecondary packaging has very low permeability to oxygen, and an oxygenabsorber, wherein the oxygen absorber removes the oxygen present at thetime of packaging assembly at a rate of up to 60%, up to 70%, up to 80%,up to 90%, or up to 100% per day in the secondary packaging and up to60%, up to 70%, up to 80%, up to 90%, or up to 100% per month in theprimary packaging container.

In some embodiments of the pharmaceutical packaging system, the primarypackaging container is a syringe, cartridge, vial or drug storagecontainer. In certain instances, the primary packaging container is asyringe. In some embodiments, the primary packaging container is plasticor glass. In certain instances, the primary packaging container isglass. In some embodiments, the oxygen permeable component is an oxygenpermeable cap. In some embodiments, the oxygen permeable component isrubber or plastic. In some embodiments, the oxygen permeable componentis a rubber cap.

In some embodiments of pharmaceutical packaging system, the secondarypackaging is a bag or blister packaging. In some embodiments, thesecondary packaging comprises an oxygen barrier material selected fromthe group consisting of high density polyethylene (HDPE), ethylene/vinylalcohol copolymer (EVOH), polypropylene (PP), polyethylene terephthalate(PET), polyethylene naphthalate (PEN), and polyamide (PA), metalizedfilm, aluminum foil, oxide coated films and combinations thereof. Incertain instances, the oxygen barrier material is EVOH. In someembodiments, the secondary packaging material comprises a top and bottomweb. In certain instances, the bottom web is a thermoformed blister. Incertain instances, the thermoformed blister comprises EVOH. In certaininstances, the top web is aluminum foil or an EVOH layer.

In some embodiments of pharmaceutical packaging system, the oxygenabsorber is placed inside the secondary packaging. In certain instances,the oxygen absorber is a sachet, pouch, canister, capsule, label,sticker, strip, patch, cartridge or container. In some embodiments, theoxygen absorber is incorporated into the material of the secondarypackaging. In some embodiments, the oxygen absorber is a coating orlayer that lines the secondary packaging. In some embodiments, theoxygen absorber is selected from the group consisting of reduced ironcompounds, catechol, ascorbic acid and analogs thereof, metal ligands,unsaturated hydrocarbons and polyamides. In certain instances, theoxygen absorber is a reduced iron compound.

In some embodiments of pharmaceutical packaging system, the oxygenabsorber reduces the oxygen level from the time of packaging assembly toabout zero percent in about one to seven days, or one to three days inthe secondary packaging and in about one to six months, or one to threemonths in the primary packaging container. In some embodiments, oxygenabsorber reduces the oxygen level from the time of packaging assembly toabout zero percent in about one day in the secondary packaging and inabout one month in the primary packaging container. In some embodiments,the oxygen levels in the primary and secondary packaging remain at aboutzero percent after the initial reduction in the primary and secondarypackaging for at least one year. In some embodiments, the oxygen levelsin the primary and secondary packaging remain at about zero percentafter the initial reduction in the primary and secondary packaging forat least three years.

In some embodiments of pharmaceutical packaging system, theoxygen-sensitive drug is selected from the group consisting of morphine,hydromorphone, promethazine, dopamine, epinephrine, norepinephrine,esterified estrogen, ephedrine, pseudoephedrine, acetaminophen,ibuprofen, danofloxacin, erythromycin, penicillin, cyclosporine,methyldopate, cetirizine, diltiazem, verapamil, mexiletine,chlorothiazide, carbamazepine, selegiline, oxybutynin, vitamin A,vitamin B, vitamin C, L-cysteine and L-tryptophan. In certain instances,the oxygen-sensitive drug is morphine. In certain instances, theoxygen-sensitive drug is hydromorphone. In certain instances, theoxygen-sensitive drug is promethazine.

In another aspect, the pharmaceutical packaging system comprises aprimary packaging container comprising an oxygen-sensitive drug, whereinthe primary packaging container has an oxygen permeable component andwherein the primary packaging container is packaged under inertconditions, a hermetically sealed secondary packaging which envelops theprimary packaging container, wherein the secondary packaging has verylow permeability to oxygen, and an oxygen absorber, wherein the oxygenabsorber, after removal of the oxygen present at the time of packagingassembly, maintains an oxygen level of about zero percent in thesecondary packaging and an oxygen level of about zero percent in theprimary packaging container for about one year. In some embodiments, theoxygen levels in the primary and secondary packaging remain at aboutzero percent after the initial reduction in the primary and secondarypackaging for at least one year. In some embodiments, the oxygen levelsin the primary and secondary packaging remain at about zero percentafter the initial reduction in the primary and secondary packaging forat least three years.

Also provided herein is a pharmaceutical packaging system for aninjectable oxygen-sensitive drug, the packaging system comprising asyringe filled under inert conditions with an injectableoxygen-sensitive drug, wherein the syringe has an oxygen permeable tipcap, a hermetically sealed blister packaging which houses the syringe,wherein the blister packaging comprises a multilayer bottom web and amultilayer top web lid; and an oxygen absorber, wherein the oxygenabsorber reduces the oxygen level present from the time of packagingassembly to about zero percent in about one to three days in the blisterpackaging and in about one to three months in the syringe.

In some embodiments, the syringe is plastic or glass. In someembodiments, the secondary packaging material is a thermoformed,aluminum-based cold formed, or molded blister. In some embodiments, themultilayer bottom web comprises ethylene/vinyl alcohol copolymer (EVOH).In some embodiments, the top web lid comprises aluminum foil or EVOH.

In some embodiments, oxygen absorber is placed inside the blisterpackaging. In certain instances, oxygen absorber is a canister. In someembodiments, the oxygen absorber has a capacity to absorb about 30 ccoxygen at 1 atm. In some embodiments, the oxygen absorber is iron-based.In some embodiments, the oxygen absorber reduces the oxygen level in theblister packaging from the time of packaging assembly to about zeropercent at about one day. In some embodiments, the oxygen absorberreduces the oxygen level in the syringe from the time of packagingassembly to about zero percent at about one month. In some embodiments,the oxygen level remains at about zero percent in the syringe and theblister packaging for at least three years.

In some embodiments, the injectable oxygen-sensitive drug is morphine.In some embodiments, the injectable oxygen-sensitive drug ishydromorphone. In some embodiments, the injectable oxygen-sensitive drugis promethazine.

Also provided herein is a pharmaceutical packaging system for injectablemorphine, the packaging system comprising a syringe filled under inertconditions with morphine, wherein the syringe has an oxygen permeabletip cap, a hermetically sealed blister packaging which houses thesyringe, wherein the blister packaging comprises a multilayer bottom weband a multilayer top web lid; and an oxygen absorber, wherein the oxygenabsorber reduces the oxygen level from the time of packaging assembly toabout zero percent in about one to three days in the blister packagingand in about one to three months in the syringe.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings:

FIG. 1: Schematic of exemplary packaging system embodiments with oxygenabsorber in a sachet (a), in the lid (b), in a canister (c) andpositioned on the primary packaging (d).

FIG. 2: Schematic depicting a packaging system having (1) oxygen barriersecondary packaging, (2) oxygen absorber, and (3) primary packaging(syringe) along with oxygen transfer rates of the various environments.

FIG. 3: Drawing of an exemplary syringe and secondary packagingembodiment where a secondary packaging includes a first compartment toreceive a syringe barrel and second compartment to receive a plunger rodseparate and detached from the syringe barrel.

FIG. 4: Oxygen levels in pouch environments for packaging configurationsA, C, D and O stored at 25° C./60% Relative Humidity (RH).

FIG. 5: Oxygen levels in syringe barrels for packaging configurations A,C and D stored at 25° C./60% RH.

FIG. 6: Comparison of oxygen levels in syringe barrels versus pouchenvironments for packaging configuration A stored at 25° C./60% RH.

FIG. 7: Oxygen levels in pouch environments for packaging configurationsE, E bis, F and G stored at 25° C./60% RH.

FIG. 8: Oxygen levels in pouch environments for packaging configurationsE, E bis, F and G stored at 25° C./60% RH for the first 8 days.

FIG. 9: Oxygen levels in syringe barrels for packaging configurations E,F and G stored at 25° C./60% RH.

FIG. 10: Oxygen levels in pouch environments of defective pouches ofconfigurations E and G stored at 25° C./60% RH.

FIG. 11: Oxygen levels in blister environments for packagingconfigurations 1 (♦), 2 (▪), and 3 (▴) stored at 25° C./60% RH.

FIG. 12: Oxygen levels in syringe environments for packagingconfigurations 1 (♦), 2 (▪), and 3 (▴) stored at 25° C./60% RH.

FIG. 13: Oxygen levels in a syringe of various fill and packagingconditions over the course of a year.

FIG. 14: Pseudomorphine content of 2 mg/mL morphine formulation fromExample 5 stored at 40° C./75% RH.

FIG. 15: Pseudomorphine content of 2 mg/mL morphine formulations in (♦)standard packaging and (▪) oxygen barrier packaging stored in (top)ambient (25° C./60% RH) or (bottom) accelerated (40° C./75% RH) storageconditions.

FIG. 16: Unknown impurity content of 1 mg/mL (top) or 10 mg/mL (bottom)hydromorphone formulations in (♦) standard packaging and (▪) oxygenbarrier packaging stored in accelerated (40° C./75% RH) storageconditions.

FIG. 17: Sulfoxide content of 25 mg/mL promethazine formulations in (♦)standard packaging and (▪) oxygen barrier packaging stored in (top)ambient (25° C./60% RH) or (bottom) accelerated (40° C./75% RH) storageconditions.

DETAILED DESCRIPTION OF THE INVENTION

Provided herein are pharmaceutical packaging systems for prefilledliquid medicament containers having an oxygen permeable component. Thepackaging systems described herein are useful for enhancing stabilityand preventing oxidative degradation of oxygen sensitive drugs in liquidform thereby allowing for extended product shelf life and prolonged drugpotency or efficiency.

“Oxygen-sensitive” or “oxygen-sensitivity” refers to the ability of asubstance to react with oxygen under ambient temperature conditions(e.g., 5° C. to about 40° C.). The chemical reaction may involve theaddition of an oxygen atom to the substance, removal of a hydrogen fromthe substance, or the loss or removal of one or more electrons from amolecular entity, with or without concomitant loss or removal of aproton or protons.

In one aspect, the pharmaceutical packaging systems herein comprise amedicament container as a primary packaging having permeability tooxygen and houses a liquid oxygen sensitive drug; a secondary packagingwhich envelops the primary packaging and has very low permeability tooxygen and an oxygen absorber that is placed inside or incorporated intothe secondary packaging. FIG. 1 illustrates different configurations ofthe pharmaceutical packaging system embodiments with an oxygen absorber(2) as a sachet (FIG. 1 a) placed inside the secondary packaging (1) andunder the syringe primary packaging (3), in the lid 4 (FIG. 1 b) ofsecondary packaging (1) and as a canister (FIG. 1 c) placed next to thesyringe primary packaging. Another embodiment where the oxygen absorberis positioned directly on the syringe primary packaging is alsoillustrated (FIG. 1 d). In this case the oxygen absorber can be glued,or bonded directly on the surface of the primary packaging or evenintegrated in the thickness of the primary packaging. Additionalconfigurations are within the scope of the pharmaceutical packagingsystems herein.

A feature of the pharmaceutical packaging systems herein is that theconfiguration allows the absorption and removal of oxygen in all thecomponents of the system. As the examples show, the oxygen absorberexpectedly removes the oxygen from the secondary packaging. However,surprisingly, the oxygen absorber also removes oxygen from the primarypackaging container and the liquid as it will be depicted in Example 3.FIG. 2 depicts the oxygen removal of an exemplary pharmaceuticalpackaging system. Here, the oxygen absorber (2) is placed inside thepharmaceutical packaging system. Therefore, it removes oxygen within theinitial air volume present in the secondary packaging (1) at a hightransfer rate R3. The absorber also removes the oxygen within theprimary packaging container (3) and its contents (in this case asyringe) at a moderately lower transfer rate R2. This oxygen removal isfacilitated by the oxygen permeable component of the primary packagingcontainer. Finally, the oxygen absorber of the packaging system removesoxygen from ingress through the secondary packaging over the packaging'sshelf life. As the secondary packaging is composed of material that hasvery low permeability to oxygen, the oxygen transfer rate R1 from theenvironment outside the secondary packaging is very low.

In essence, the oxygen absorber in the pharmaceutical packaging systemherein leads to the absorbance and removal of oxygen in the secondarypackaging, the primary packaging and the drug inside the primarypackaging. The oxygen absorber further removes the low oxygen ingressthrough the secondary packaging over time. In this configuration, theresidual oxygen amount that is present inside the primary and secondarypackaging due to the pharmaceutical manufacturing process as well as theoxygen entering the packaging system from external environments overtime, is reduced and even eliminated.

Another feature of the pharmaceutical packaging systems described hereinis the pharmaceutical packaging system maintains zero % oxygen levelafter removal of the initial oxygen in the primary packaging containerand secondary packaging for an extended period of time. As a result, thepharmaceutical packaging systems described herein offer increases in theshelf life of oxygen sensitive drugs past conventional packaging andmethods such as from inert atmosphere packaging processes (e.g.,nitrogen blanketing and/or degassing). In some embodiments, thepharmaceutical packaging systems described herein maintains zero %oxygen level in the primary and secondary packaging for at least about12 months, at least about 15 months, at least about 18 months, at leastabout 24 months, at least about 30 months, at least about 36 months, atleast about 48 months or at least about 60 months. In certain instances,the pharmaceutical packaging systems described herein maintains zero %oxygen level in the primary and secondary packaging for at least 12months. In certain instances, the pharmaceutical packaging systemsdescribed herein maintains zero % oxygen level in the primary andsecondary packaging for at least 24 months. In certain instances, thepharmaceutical packaging systems described herein maintains zero %oxygen level in the primary and secondary packaging for at least 36months.

Primary Packaging

The primary packaging container of the pharmaceutical packaging systemsdescribed herein houses or contains the oxygen sensitive drug in liquidform. Various types of containers are suitable for the containment ofoxygen sensitive drugs. Examples of such containers include, withoutlimitation, vials, syringes, ampoules, bottles, cartridges, carpules andi.v. bags or pouches. In some embodiments, the primary packagingcontainer of pharmaceutical packaging systems described herein areselected from a vial, syringe, ampoule, bottle, cartridge, carpule and abag.

Vials for the containment of the oxygen sensitive drugs generally haveopen mouths which are normally closed with an elastomer closure throughwhich a hollow needle may be passed and via which liquid may beintroduced or removed from the vial. Vials are typically made of type Iglass or may be made of plastic such as PET. Suitable elastomers forsuch closures include, for example, vulcanized elastomers and styrenicblock copolymer thermoplastic elastomers, but also natural rubber,acrylate-butadiene rubber, cis-polybutadiene, chlroro or bromobutylrubber, chlorinated polyethylene elastomers, polyalkylene oxidepolymers, ethylene vinyl acetate, fluorosilicone rubbers,hexafluoropropylene-vinylidene fluoride-tetrafluoroethylene terpolymers,butyl rubbers, polyisobutene, synthetic polyisoprene rubber, siliconerubbers, styrene-butadiene rubbers, tetrafluoroethylene propylenecopolymers, thermoplastic-copolyesters, thermo-plastic elastomers, orthe like or a combination thereof.

Syringes generally comprise a cylindrical barrel, often made of glassbut more recently have been made of plastic materials, for example,cyclic olefin polymers or acrylonitrile butadiene styrene (ABS),polycarbonate (PC), polyoxymethylene (POM), polystyrene (PS),polybutylene terephthalate (PBT), polypropylene (PP), polyethylene (PE),polyamide (PA), thermoplastic elastomer (TPE) and their combinations.The barrels of such syringes are operated with an elastomer plungerwhich can be urged along the barrel to eject liquid content via anozzle. Suitable elastomers for such plungers may be based on the samethermoplastic elastomers as mentioned above for vial closures. Ampoulesare a type of sealed vial which are generally opened by snapping off theneck or the top of the ampoule. Cartridges and carpules are specializedcontainers that are inserted into a drug delivery device (e.g. syringeor autoinjector). Finally, intravenous bags and pouches are typicallyused for infusion therapy or multiple dose administration.

For the more rigid primary packaging containers, glass is a suitablematerial as it provides various benefits. Glass is generally consideredto not be permeable to moisture and oxygen permeation. An alternativegroup of materials, cyclic olefin polymers, polypropylene orpolyethylene terephthalate are suitable for the containers as theytypically have less breakage concerns as compared to glass and stillexhibit good transparency. These materials include cyclic olefincopolymers such as Topas™ polymer (Topas Advanced Polymers GmbH) andcyclic olefin homopolymers such as Crystal Zenith™ polymer (Dalkyo). Forflexible primary packaging containers such as bags, materials suitableinclude those having oxygen barrier properties.

Regarding drugs with sensitivity to light, the primary packagingcontainer should have light barrier properties that can be achieved witha colorant to produce a colored (e.g., amber, dark blue) or opaqueprimary packaging container. A primary packaging made of transparentmaterials may also be suitable provided it is placed in secondary ortertiary packaging materials that are opaque to light.

In one embodiment of the pharmaceutical packaging systems describedherein, the primary packaging container is a syringe. Syringes, and inparticular hypodermic syringes, are useful in the medical field fordispensing fluids, including medications. A conventional syringetypically includes a syringe barrel with in an opening at one and aplunger mechanism disposed through the opposite end. Syringes in thepharmaceutical packaging systems described herein contain the liquiddrug for dispensing and are stored overtime once filled. They arereferred to as “pre-filled” syringes. An advantage of the pre-filledsyringe is that the drug is filled at a proper dose and can be deliveredto a patient quickly over conventional methods of filling the syringewith the liquid drug in a vial prior to administration, thereby savingtime, maintaining consistent dosing and volumes for delivery and endingcontamination and degradation issues of multiple dose drug vials.Exemplary syringes for use in the pharmaceutical packaging systemsdescribed herein include those described in U.S. Pat. Nos. 6,196,998;6,200,627; 6,217,550; 6,743,216; 7,141,042; 8,075,535; and 8,652,094;and U.S. Pat. Appl. No. 2013/0081974 each of which is incorporated byreference for their disclosure relating to syringe assembly.

In the pharmaceutical packaging systems described herein, the primarypackaging container also has an oxygen permeable component.“Oxygen-permeable” as used herein refers to materials which allow thepassage of oxygen through the material. Certain rubbers, plastics andpapers have oxygen-permeable properties and can be molded into stoppers,caps, seals, membranes and other components which may be structural orprotective. When an oxygen-permeable component separates two differentoxygen level environments, the oxygen-permeable component allows thepassage of oxygen from the higher oxygen level environment to the loweroxygen level environment. Over time, the two environments equilibratewith respect to oxygen levels. Usually, these materials are alsopermeable to other gases. As such, the oxygen-permeable component allowsfor sterilization processes such as via gas (e.g., ethylene oxide) orsteam sterilization. For example, a syringe primary packaging containercan have a tip cap that is gas or oxygen-permeable which allowssterilization of the syringe interior, and if the syringe is filled,also the drug itself. Accordingly, in some embodiments, the primarypackaging container is a syringe that has an oxygen-permeable tip capwhich can be a single material tip cap or a bi-material tip cap. In anexemplary embodiment, the syringe oxygen-permeable tip cap includes arubber part. Exemplary tip caps include those described in U.S. Pat.Nos. 5,624,402; 6,027,482 and 6,190,364, each of which is incorporatedby reference for their disclosure relating to tip caps.

Secondary Packaging

The secondary packaging component of the pharmaceutical packagingsystems described herein envelops or surrounds the primary packagingcontainer that holds the liquid drug. In the embodiments herein, afterplacement of the primary packing container into the secondary packaging,the secondary packaging is sealed to prevent any contamination as wellas ingress of oxygen. To prevent further ingress of oxygen into thesecondary packaging, the secondary packaging is composed with an oxygenbarrier material which that has very low permeability to oxygenmolecules. The secondary packaging can be of any packaging type suitablefor the primary packaging container, the types which includes, withoutlimitation, a bag, a pouch, a box, a bag, a blister, a canister, abottle and the like. As such, the secondary packaging may be rigid orflexible and of any shape and size. The exact requirements of asecondary packaging depends on a variety of factors, including thechemical nature of the drug inside the primary packaging container,amount and type of the oxygen absorber, physical configuration of theprimary packaging container, hermetic sealing method, nitrogenblanketing, vacuumization and/or other modified atmosphere inside thesecondary packaging, initial oxygen concentration inside the secondarypackaging, intended shelf life of the drug, etc.

Oxygen barrier materials for the secondary packaging have very lowpermeability to oxygen molecules (e.g., ˜1 or less cm³O₂/m² per day,atm). Non-limiting examples of oxygen barrier materials suitable for thesecondary packing include ethylene vinyl alcohol (EVOH), polyvinylalcohol (PVOH), polyvinyl chloride (PVC), polyvinylidene chloride(PVDC), polychlorotrifluoroethylene (PCTFE), vinylidene chloride/methylacrylate copolymer, polyamide, and polyester. Metal foil (e.g.,aluminum) or SiOx compounds can be used to provide very low permeabilityto oxygen in the secondary packaging. Metalized films can include asputter coating or other application of a metal layer such as aluminumto a polymeric substrate such as high density polyethylene (HDPE), lowdensity polyethlyene (LDPE), ethylene/vinyl alcohol copolymer (EVOH),polypropylene (PP), polyethylene terephthalate (PET) including amorphousforms (APET) and glycol modified forms (PET-G), polyethylene naphthalate(PEN), ethylene acrylic acid copolymer (EAA), and polyamide (PA).Alternatively, oxide coated webs (e.g., aluminum oxide or silicon oxide)can be used to provide very low permeability to oxygen in the secondarypackaging. Oxide coated films can include a coating or other applicationof the oxide, such as alumina or silica, to a polymeric substrate suchas high density polyethylene (HDPE), low density polyethlyene (LDPE),ethylene/vinyl alcohol copolymer (EVOH), polypropylene (PP),polyethylene terephthalate (PET) including amorphous forms (APET) andglycol modified forms (PET-G), polyethylene naphthalate (PEN), ethyleneacrylic acid copolymer (EAA), and polyamide (PA). In some embodiments,the secondary packaging comprises an oxygen barrier material selectedfrom the group consisting of EVOH, PVOH, PVC, PVDC, PCTFE, vinylidenechloride/methyl acrylate copolymer, polyamide, polyester, a metalizedfilm, oxide coated films, and combinations thereof.

Embodiments of the oxygen barrier materials can be present in the formof multilayer films. Multilayer films (e.g., 2, 3, 4, 5 or 6 layerfilms) can comprise one or more of the previously described oxygenbarrier material(s), and may include additional layers of non-barriermaterials such as PET, polyethylene (PE) and/or coated (e.g., clay, wax,plastic, or the like) or uncoated paper. Suitable multilayer filmsinclude, but are not limited to, PVC/EVOH, PET/EVOH, PET/EVOH/PE,PET/EVOH/PET, PE/EVOH/PE, PVC/PCTFE/EVOH, Paper/Aluminum (Alu)/PE,PET/Alu/PE, Paper/PE/foil/PE, Paper/PET/Alu, Clay-coatedpaper/PE/foil/LDPE, Paper/LDPE/foil/EEA, and related films thereof.Layers can be bonded together via the use of adhesives, for example, apolyolefin blend (mixture of poly(α-olefins), or polyamide resins. Insome embodiments, the secondary packaging comprises an oxygen barriermaterial as a multilayer film. In certain instances the multilayer filmis PVC/EVOH, PET/EVOH, PET/EVOH/PE, PET/EVOH/PET, PE/EVOH/PE,PVC/PCTFE/EVOH, Paper/Aluminum (Alu)/PE, PET/Alu/PE, Paper/PE/foil/PE,Paper/PET/Alu, Clay-coated paper/PE/foil/LDPE or Paper/LDPE/foil/EEA.

Multilayer films are made by any known method, including conventionalextrusion, coextrusion, and/or lamination processes. Likewise,conventional manufacturing processes can be used to make a bag, a pouch,a box, a bag, a blister, a canister, a bottle or other container fromthe oxygen barrier materials for the secondary packaging as well as toprovide hermetic sealing. Hermetic sealing has importance in thepharmaceutical packaging systems described herein to maintain thereduced oxygen level. Indeed, when the secondary packaging is improperlysealed or leaking, the oxygen level can increase rapidly to 21% afteroxygen scavenger is fully at capacity as demonstrated in Example 4.Optionally, in some embodiments, the hermetic sealing occurs under aninert environment (e.g., nitrogen blanket) to reduce the initial oxygenlevels in the secondary packaging's air volume.

In some embodiments, the secondary packaging is a blister packaging.Blister packaging is known in the packaging industry and commonly usedfor packaging pharmaceuticals and medical devices such as solid dosageforms (tablets, capsules, etc.), transdermal patches, syringes, and thelike. The term “blister” refers to a bottom web substrate that is rigidand has one or more recesses that conform and can hold in place thecontents being packaged (in this case the primary packaging container).The recesses can be formed by thermoforming, a deforming process such asan aluminum-based cold forming process or by injection molding. For thepharmaceutical packaging systems described herein where the secondarypackaging is a blister packaging, bottom web substrate comprises anoxygen barrier material (e.g., multilayer film with an EVOH layer).Depending on materials used and on the nature of the drugs stored insidethe primary packaging, bottom web substrate can be transparent or opaquewith the use of colorants.

Another component of a blister packaging is a top web laminate (“lid”)which is laminated to the blister by heat seal. The top web lid isusually flexible and can be peeled off the blister to allow access tothe packaged contents. For embodiments where the secondary packaging isa blister packaging, the top web lid also comprises an oxygen barriermaterial, such as metal (e.g., aluminum) foil. In certain instances, thetop web lid comprises a multilayer film having an aluminum layer and oneor more additional layers. Additional layers include coated or uncoatedpaper, PE and/or PET layers. In certain instances, the top web lidcomprises a film comprising paper, aluminum and PET layers. The top weblid also comprises a laminate for sealing the blister. The laminate isapplied to the lid by methods known in the packaging industry includingcoating, extrusion and lamination. One type of laminate is aheat-sealable laminate (e.g., thermo-plastic coating). The top lidlaminate also encompasses other adhesive technologies, includingpressure sensitive adhesives, photo-curing adhesives and two component(e.g., epoxy) adhesives.

In an exemplary embodiment, the secondary packaging comprises of ablister packaging having a thermoformed transparent shell made of amultilayer plastic film that includes EVOH (bottom web), and amultilayer paper-plastic heat salad lid material including an aluminumlayer (top web).

In a further embodiment, a secondary packaging container suitable forthe pharmaceutical packaging systems described herein is provided whichincludes a first compartment to receive a syringe barrel and secondcompartment to receive a plunger rod separate and detached from thesyringe barrel. With the syringe barrel received in the firstcompartment and the plunger rod received within the second compartment,the sealing member of the plunger rod seals the syringe barrel and theplunger rod within the secondary packaging. This secondary packagingcontainer configuration allows for reduced storage space of the syringe.In this manner, upon removal of the plunger rod and the syringe barrelfrom the secondary packaging, the plunger rod can quickly and easily besecured to the syringe barrel via a stopper for delivery of a drugformulation contained inside the syringe. An exemplary syringe andsecondary packaging configuration is depicted in FIG. 3. FIG. 3 shows asyringe barrel (30) containing a drug formulation with a sealing cap(20) and a flange (40) for a user's fingers received in a firstcompartment portion (108) and a plunger rod (14) received in a secondcompartment portion (94) of a secondary packaging (92). The plunger rod(14) can comprise elastic fingers (160) which lock and secure to thesyringe barrel (30), a flange (66) for usability, key slots (78) forsecuring the plunger rod in the second compartment of the secondarypackaging and vents (76) to allow oxygen removal with an oxygen absorber(not shown). The secondary packaging with the syringe components issealed with a sealing cover (190). Additional secondary packagingconfigurations for pharmaceutical packaging systems described herein arefound in U.S. Pat. Appl. No. 2013/0080974, which is incorporated byreference for the relating to syringe and packaging assembly.

Oxygen Absorber

In the pharmaceutical packaging systems described herein, oxygenabsorbers absorb and remove oxygen from all components of the system.Oxygen absorbers are contemplated to be in any size or shape includingsachet, pouch, capsule, label, strip, patch, canister, cartridge,lining, sticker, etc. that is placed inside of the secondary packagingas well as part of the secondary packaging itself but can also beintegrated to the primary packaging. In some embodiments, the oxygenabsorber is in the form of a sachet. In other embodiments, the oxygenabsorber is in the form of a canister. In some other embodiments, theoxygen absorber is in the form of a label. In yet other embodiments, theoxygen absorber is in the form of a strip. In further embodiments, theoxygen absorber is a sticker or label that adheres to the secondarypackaging or to the primary packaging. In yet further embodiments, theoxygen absorber is incorporated as part of the secondary packagingitself such as lid, film, or seal of the secondary packaging.Non-limiting examples of secondary packaging and oxygen absorberconfigurations are depicted in FIG. 1. An exemplary secondary packagingwith an oxygen absorber for a morphine formulation is described inExample 8.

Suitable materials for oxygen absorbers include metal-based substancesthat remove oxygen by reacting with it by chemical bonding, generallyforming a metal oxide component. Metal-based substances includeelemental iron as well as iron oxide, iron hydroxide, iron carbide andthe like. Other metals for use as oxygen absorbers include nickel, tin,copper and zinc. Metal-based oxygen absorbers are typically in the formof a powder to increase surface area. Powder formation of themetal-based oxygen absorbers is by any known method including, but notlimited to, atomization, milling, pulverization, and electrolysis.Additional materials for oxygen absorbers include low molecular weightorganic compounds such as ascorbic acid, sodium ascorbate, catechol andphenol, activated carbon and polymeric materials incorporating a resinand a catalyst. In some embodiments of the pharmaceutical packagingsystem, the oxygen absorber is a metal-based oxygen absorber. In certaininstances of the pharmaceutical packaging system, the oxygen absorber isan iron-based oxygen absorber. In further instances of thepharmaceutical packaging system, the oxygen absorber is an iron-basedoxygen absorber in the form of a canister.

Oxygen Absorbers and Secondary Packaging

A feature of the oxygen absorber in the pharmaceutical packaging systemsherein is the rapid uptake of oxygen present in the secondary packaging.Oxygen in air at ambient temperature and pressure (1 atm) is at aconcentration of about 21%. When a pharmaceutical packaging systemdescribed herein is assembled in air in ambient conditions, theenvironment inside the secondary packaging is initially also at 21%oxygen level. In Example 3 and FIGS. 7 and 8, the oxygen absorber in thepharmaceutical packaging system quickly reduces the oxygen level in thesecondary packaging to zero % in one to three days. Accordingly, in someembodiments, the oxygen absorber reduces oxygen to zero % in thesecondary packaging in about seven days, in about six days, in aboutfive days, in about four days, in about three days, in about two days,or in about one day after initial packaging assembly. In someembodiments, the oxygen absorber reduces oxygen to zero % in thesecondary packaging in about one to seven days. In some embodiments, theoxygen absorber reduces oxygen to zero % in the secondary packaging inabout one to three days. In some embodiments, the oxygen absorberreduces oxygen in the secondary packaging by about 35%, about 50%, about60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%,or about 95% of the total oxygen in the air per day after initialpackaging assembly. In certain instances, the oxygen absorber reducesoxygen in the secondary packaging by about 50% per day. In otherinstances, the oxygen absorber reduces oxygen in the secondary packagingby about 75% per day. In further instances, the oxygen absorber reducesoxygen in the secondary packaging by about 90% per day. In otherembodiments, the oxygen absorber reduces oxygen in the secondarypackaging by about 35% to about 75%, about 50% to about 80%, or about65% to about 90% per day after initial packaging assembly.

In further embodiments, the oxygen absorber reduces about 2 to about 10cc of oxygen/day, atm; about 3 to about 8 cc of oxygen/day, atm; orabout 4 to 6 cc of oxygen/day, atm in the secondary packaging. Incertain instances, the oxygen absorber reduces about 2, about 3, about4, about 5, about 6, about 7, about 8, about 9, or about 10 cc ofoxygen/day, atm in the secondary packaging. In some instances, theoxygen absorber reduces about 4 cc of oxygen/day, atm. In otherinstances, the oxygen absorber reduces about 6 cc of oxygen/day, atm. Infurther instances, the oxygen absorber reduces about 8 cc of oxygen/day,atm.

Another feature of the oxygen absorber is that it maintains zero %oxygen level after removal of the initial oxygen in the secondarypackaging for an extended period of time. In some embodiments, theoxygen absorber maintains zero % oxygen level in the secondary packagingfor the entire shelf life of the drug. In some embodiments, the oxygenabsorber maintains zero oxygen level in the secondary packaging for atleast about 12 months, at least about 15 months, at least about 18months, at least about 24 months, at least about 30 months, at leastabout 36 months, at least about 48 months or at least about 60 months.In certain instances, the oxygen absorber maintains zero % oxygen levelin the secondary packaging for at least 12 months. In certain instances,the oxygen absorber maintains zero % oxygen level in the secondarypackaging for at least 24 months. In certain instances, the oxygenabsorber maintains zero % oxygen level in the secondary packaging for atleast 36 months.

Oxygen Absorbers and Primary Packaging

An advantageous feature of the oxygen absorber in the pharmaceuticalpackaging systems herein is the absorbance and removal of oxygen presentin the primary packaging and in the liquid drug itself. Surprisingly, itwas found that the oxygen absorber in exemplary packaging systems alsoremoved residual oxygen in the primary packaging and in the liquid overtime to zero % oxygen level. Degassed liquids by nitrogen bubbling stillcontain approximately 1% residual oxygen level, or approximately 400parts per billion (ppb) oxygen, or approximately a partial pressure of7.6 mmHg. As it will be illustrated and described later in thedescription referring to Example 3 and FIG. 9, the oxygen absorber inexemplary pharmaceutical packaging systems reduced the residual oxygenlevel (approximately %1) in the primary packaging and the liquid insideto zero % in one to three months. Thus, in some embodiments, the oxygenabsorber reduces oxygen to zero % in the primary packaging in aboutthree months, in about two months, or in about one month after initialprimary packaging assembly under inert conditions. In some embodiments,the oxygen absorber reduces oxygen in the primary packaging by about35%, about 50%, about 60%, about 65%, about 70%, about 75%, about 80%,about 85%, about 90%, or about 95% of the residual oxygen per monthafter initial primary packaging assembly under inert conditions. Incertain instances, the oxygen absorber reduces oxygen in the primarypackaging by about 50% per month. In other instances, the oxygenabsorber reduces oxygen in the primary packaging by about 75% per month.In further instances, the oxygen absorber reduces oxygen in the primarypackaging by about 90% per month. In other embodiments, the oxygenabsorber reduces oxygen in the primary packaging by about 35% to about75%, about 50% to about 80%, or about 65% to about 90% per month.

In other embodiments, the oxygen absorber reduces oxygen in the primarypackaging by about 150 ppb oxygen, about 200 ppb oxygen, about 250 ppboxygen, about 300 ppb oxygen, about 350 ppb oxygen or about 400 ppboxygen in the liquid contained in the primary packaging per month afterinitial primary packaging assembly under inert conditions. In certaininstances, the oxygen absorber reduces oxygen in the liquid contained inthe primary packaging by about 200 ppb oxygen per month. In otherinstances, the oxygen absorber reduces oxygen in the liquid contained inthe primary packaging by about 300 ppb oxygen per month. In furtherinstances, the oxygen absorber reduces oxygen in the liquid contained inthe primary packaging by about 400 ppb oxygen per month. In otherembodiments, the oxygen absorber reduces oxygen in the liquid containedin the primary packaging by about 150 ppb to about 300 ppb oxygen, about250 ppb to about 350 ppb oxygen, or about 300 ppb to about 400 ppboxygen per month after initial primary packaging assembly under inertconditions.

In further embodiments, the oxygen absorber reduces the oxygen partialpressure in the primary packaging by about 2.5 mmHg, about 3.0 mmHg,about 3.5 mmHg, about 4.0 mmHg, about 4.5 mmHg, about 5.0 mmHg, about5.5 mmHg, about 6.0 mmHg, about 6.5 mmHg, about 7.0 mmHg or about 7.5mmHg in the liquid contained in the primary packaging per month afterinitial primary packaging assembly under inert conditions. In certaininstances, the oxygen absorber reduces oxygen partial pressure in theliquid contained in the primary packaging by about 2.5 mmHg per month.In other instances, the oxygen absorber reduces oxygen partial pressurein the liquid contained in the primary packaging by about 5.0 mmHg permonth. In further instances, the oxygen absorber reduces oxygen partialpressure in the liquid contained in the primary packaging by about 7.5mmHg per month. In other embodiments, the oxygen absorber reduces oxygenpartial pressure in the liquid contained in the primary packaging byabout 2.5 mmHg to about 5.0 mmHg, about 3.5 mmHg to about 6.0 mmHg, orabout 5.0 mmHg to about 7.5 mmHg per month after initial primarypackaging assembly under inert conditions.

The oxygen absorber, in some embodiments, also maintains zero % oxygenlevel after removal of the initial oxygen in the primary packaging foran extended period of time. In some embodiments, the oxygen absorbermaintains zero % oxygen level in the primary packaging for the entireshelf life of the drug. In some embodiments, the oxygen absorbermaintains zero % oxygen level in the primary packaging for at leastabout 12 months, at least about 15 months, at least about 18 months, atleast about 24 months, at least about 30 months, at least about 36months, at least about 48 months or at least about 60 months. In certaininstances, the oxygen absorber maintains zero % oxygen level in theprimary packaging for at least 12 months. n certain instances, theoxygen absorber maintains zero % oxygen level in the primary packagingfor at least 24 months. In certain instances, the oxygen absorbermaintains zero % oxygen level in the primary packaging for at least 36months.

An interesting property of the pharmaceutical packaging systems herein,is that after removal of oxygen in the primary and secondary packagingby the oxygen absorber, the air pressure in the secondary packagingenvironment achieves lower than atmospheric pressure, such that there isvacuum effect.

Oxygen Absorber Capacities

The capacity for absorbing oxygen for the oxygen absorbers of thepharmaceutical packaging systems described herein encompass thecapacities sufficient to reduce the initial oxygen levels of the primaryand secondary packaging to a zero % oxygen level at a rate as describedin the previous embodiments and maintain the zero % oxygen level for aperiod of time as described in the previous embodiments. The oxygenabsorbing capacity can be optimized according to the materials used insecondary packaging, the surface area of the secondary packaging andamount of initial oxygen in the secondary and primary packaging. Forexample, the oxygen absorbing capacity of the absorber is decreased whensecondary packaging has very low permeability to oxygen whereas theoxygen absorbing capacity of the absorber is increased when secondarypackaging is made from material that is more permeable to oxygen. Thisis illustrated in more detail in Example 3 and FIG. 7. It is also withinthe scope of embodiments of the pharmaceutical packaging systemsdescribed herein, that the oxygen absorbing capacity is greater thanneeded for the total amount of oxygen over the shelf life of thepharmaceutical packaging system, i.e., overfill capacity. The extracapacity can allow for a larger buffer in the handling process forassembly of the pharmaceutical packaging system.

Exemplary oxygen absorber capacities, in some embodiments, range fromabout 10 cc (cm³, atm) to about 50 cc oxygen absorbance capacity, fromabout 15 cc to about 40 cc oxygen absorbance capacity, or from about 20to about 30 cc oxygen absorbance capacity. In some embodiments, theoxygen absorber capacity of the oxygen absorber in the pharmaceuticalpackaging system is about 10 cc, about 15 cc, about 20 cc, about 25 cc,about 30 cc, about 35 cc, about 40 cc, about 45 cc, or about 50 ccoxygen absorbance capacity. In certain instances, the oxygen absorbercapacity of the oxygen absorber in the pharmaceutical packaging systemis about 15 cc. In certain instances, the oxygen absorber capacity ofthe oxygen absorber in the pharmaceutical packaging system is about 30cc.

Packaging Assembly

In preparation of pharmaceutical packaging systems described herein, thepackaging is, in some embodiments, assembled in an environmentcontaining an inert gas, i.e., under inert packaging conditions, tolower the initial oxygen concentration in the primary and/or secondarypackaging. Under inert packaging conditions include the use of flushingor blanketing a primary and/or secondary packaging container with aninert gas as well as degassing a drug formulation by inert gas. The useof an inert gas (e.g., nitrogen, argon, CO₂, helium and the like) limitsthe drug formulation to oxygen exposure. In some embodiments, the liquiddrug formulation is also sparged or bubbled by the inert gas to removeoxygen in the liquid. The solutions are then filled and sealed intoprimary containers and, in some embodiments, secondary packaging underinert gas.

The pharmaceutical packaging systems described herein can remove oxygenfrom a primary packaging container that is packaged under ambientconditions (where the oxygen concentration is about 21%) as depicted inExample 5 and FIG. 12. However, oxygen removal from a level 21% is slow,as shown in the example, and therefore, primary packaging in ambientconditions is not recommended as the large amount of residual oxygen maycause degradation prior to its slow removal.

Oxygen Sensitive Drugs

As used herein, the term “drug” refers to a pharmaceutically activeingredient(s) and any pharmaceutical liquid composition containing thepharmaceutically active ingredient(s). Pharmaceutical liquidcompositions include forms such as solutions, suspensions, emulsions andthe like). These pharmaceutical liquid compositions can be administeredorally or by injection.

Any drug that is oxygen sensitive, i.e., can degrade as a result ofexposure to oxygen, is suitable for incorporation into thepharmaceutical packaging systems described herein. Oxygen sensitivedrugs include those that have amines either as salts or free bases,sulfides, allylic alcohols, phenols and other chemical groups that canhave reactivity with oxygen. Non-limiting examples of oxygen sensitivedrugs include morphine, hydromorphone, promethazine, dopamine,epinephrine, norepinephrine, esterified estrogen, ephedrine,pseudoephedrine, acetaminophen, ibuprofen, danofloxacin, erythromycin,penicillin, cyclosporine, methyldopate, cetirizine, diltiazem,verapamil, mexiletine, chlorothiazide, carbamazepine, selegiline,oxybutynin, vitamin A, vitamin B, vitamin C, L-cysteine, L-tryptophanand the like. In some embodiments, the primary packaging container ofthe pharmaceutical packaging systems described herein contain morphine.In other embodiments, the primary packaging container of thepharmaceutical packaging systems described herein contain hydromorphone.In further embodiments, the primary packaging container of thepharmaceutical packaging systems described herein contain promethazine.

The oxygen sensitive drugs in the pharmaceutical packaging systemsdescribed herein are stable in various storage conditions includingambient, intermediate and accelerated conditions. Stability as usedherein refers to a formulation meeting all stability criteria along itsparticular shelf life, as defined in the USP or equivalent monograph ofthe drug product (for the assay of the drug substance in particular) andthe current stability criteria of the ICH Q3B guidance for impurities.All critical quality attributes need to stay in their acceptance rangethroughout the formulation's shelf life. As an example, for a morphineformulation to be stable, assay of the drug substance, i.e., morphine,is in the [90.0%-110.0%] range as per USP and per ICH Q3B guidelines,all known, i.e., identified, degradation products, such aspseudomorphine, hydroxymorphine, norphine-N-oxide, and the like, as wellas unknown degradation products need to be no more than (NMT) 0.2%.Stability of the oxygen sensitive drugs in the pharmaceutical packagingsystems described herein is assessed by HPLC, UPLC or any other knownanalytical method.

In some embodiments an oxygen sensitive drug, when stored in thepharmaceutical packaging systems described herein, is stable in ambientconditions (e.g., 25° C./60% RH) for at least 12 months, at least 15months, at least 18 months, or at least 24 months. In certain instances,an oxygen sensitive drug, when stored in the pharmaceutical packagingsystems described herein, is stable in ambient conditions for at least24 months. In other embodiments an oxygen sensitive drug, when stored inthe pharmaceutical packaging systems described herein, is stable inintermediate conditions (e.g., 30° C./65% RH) for at least 6 months, atleast 8 months, at least 10 months or at least 12 months. In certaininstances, an oxygen sensitive drug, when stored in the pharmaceuticalpackaging systems described herein, is stable in intermediate conditionsfor at least 12 months. In further embodiments an oxygen sensitive drug,when stored in the pharmaceutical packaging systems described herein, isstable in accelerated conditions (e.g., 40° C./75% RH) for at least 4months, at least 5 months, or at least 6 months. In certain instances,an oxygen sensitive drug, when stored in the pharmaceutical packagingsystems described herein, is stable in accelerated conditions for atleast 6 months.

The pharmaceutical packaging systems described herein are also suitablefor pharmaceutical liquid compositions comprising an oxygen-sensitiveexcipient. Degradation of oxygen-sensitive excipients in apharmaceutical composition can lead to a variety of effects ranging fromdiscoloration of the composition, reduced performance or efficiency ofthe composition and/or harmful reactivity with the active pharmaceuticalingredient. Nonexclusive examples of oxygen-sensitive excipients thatbenefit from the pharmaceutical packaging systems described hereininclude polyethylene oxide (PEO) or polyethylene glycol (PEG) andpolyoxyethylene alkyl ethers.

Kits and Articles of Manufacture

For the pharmaceutical packaging systems described herein, kits andarticles of manufacture are also described. Such kits comprise each ofthe components assembled together of the pharmaceutical packaging systemand may optionally comprise an outer packaging surrounding the secondarypackaging. A kit may also unit multiple pharmaceutical packaging systemsfor a particular drug to enable multi-dosing (e.g., a kit of one week ofa daily dosed drug). Multiple pharmaceutical packaging systems in a kitmay also contain different drugs for purposes such as drug combinationsor rotations.

A kit may comprise one or more additional components such as additionaldevices, desirable from a commercial and user standpoint for thepharmaceutical packaging systems. Non-limiting examples of suchmaterials include, but not limited to, buffers, diluents, filters,needles, syringes; adaptors, waste receptacles, and/or labels listingcontents and/or instructions for use, and package inserts withinstructions for use associated with the pharmaceutical packagingsystem. A set of instructions will also typically be included.

A label can be on or associated with the secondary packaging. A labelcan be on a secondary packaging when letters, numbers or othercharacters forming the label are attached, molded or etched into thecontainer itself; a label can be associated with a secondary packagingwhen it is present within a receptacle or carrier that also holds theprimary packaging container, e.g., as a package insert. A label can beused to indicate that the contents are to be used for a specifictherapeutic application. The label can also indicate directions for useof the contents, such as in the methods described herein.

EXAMPLES Example 1 Secondary Packaging Configurations and AnalyticalEquipment

Exemplary secondary packaging were developed and analyzed with respectto oxygen levels in the subsequent Examples 2 to 4. Differentconfigurations allowed comparison of the materials' performanceregarding oxygen barrier properties; oxygen absorber behavior andperformance; and the kinetic and impact on the amount of oxygen insidethe syringe. Furthermore, two systems were tested for oxygen removal inthe secondary packaging: nitrogen flush before sealing the packaging orwith use of an oxygen absorber.

Primary Packaging Container:

Degassed water was filled into 1.25 mL glass syringes (Hypak™, BectonDickinson & Co.) with an oxygen permeable tip cap. An OxyDot® oxygensensor (visual indicator of oxygen levels) was stuck inside the syringebarrel before the filling.

Secondary Packaging:

Materials for the secondary packaging included regular APET film whichis without specific gas barrier properties; and multilayer films whichincluded an EVOH layer as a gas barrier. Selected oxygen absorbersincluded an absorber in a sachet, absorber on a sticker and absorberembedded in the web film. The eight different tested configurations aredescribed in the following table:

Configu- Bottom Top Oxygen ration Web Web Removal A APET Paper/Alu25μm/PE N₂ flush C PET/EVOH/PE PET/Alu8 μm/PE N₂ flush D PVC/PCTFE/EVOHoPA/Alu45 μm/PVC N₂ flush E APET Paper/Alu20 μm/PE O₂ absorber sachet 30cc E bis APET Paper/Alu20 μm/PE O₂ absorber label 15 cc F PET/EVOH/PEPET/Alu8 μm/PE O₂ absorber label 15 cc G PET/EVOH/PE Sealed Air OS Bytop web 12 cc O PET/EVOH/PET Paper/Alu20 μm/PE N₂ flush APET: AmorphousPolyethylene terephthalate PET: Polyethylene terephthalate EVOH:Ethylene vinyl alcohol PE: Polyethylene PVC: Polyvinyl chloride PCTFE:Polychlorotrifluoroethylene Alu: Aluminum Sealed Air OS: OxygenScavenger film delivered by Sealed Air Company

Pouches were prepared with the two films (bottom web and top web) thatencased the syringes and subsequently sealed. Four configurations wereprepared with nitrogen flush (Configurations A, C, D and O). The sealingof these pouches were performed in a glove box with a manual sealingclamp. Prior to sealing, an OxyDot® oxygen sensor was stuck inside thepouch. The other configurations contained a type of oxygen absorber(Configurations E, E bis, F and G). These were sealed in ambient airwith an O₂ level of approximately 21%. Pouch dimensions wereapproximately 130 mm×90 mm and had a volume, with the syringe inside, ofabout 30 to 35 mL.

Analytical Equipment:

The equipment used to measure the oxygen levels inside the pouches andthe syringes included an oxygen analyzer that measured the oxygen levelby reading the OxyDot® visual indicator (OxySense Analyzer) and ABL5blood gas analyzer (Radiometer) which measured the oxygen level in thewater of the syringe.

Storage:

In the following Examples 2 to 4, the syringes in the secondarypackaging were placed in a climatic chamber at 25° C./60% relativehumidity (RH).

Example 2 Oxygen Levels in Nitrogen Flushed Packaging Oxygen in PouchEnvironments

The following table depicts the oxygen levels for Configurations A, C, Dand O.

Oxygen % in Configuration Days Config 0 14 30 60 90 120 150 180 210 360A 0.06 0.44 0.93 1.83 2.62 3.34 3.98 4.6 5.18 7.91 C 0.16 0.22 0.33 0.480.65 0.8 0.97 1.14 1.24 1.91 D 0.27 0.33 0.47 0.53 0.57 0.55 0.6 0.650.65 0.79 O 0.83 0.96 1.09 1.19 1.25 1.4 1.45

FIG. 4 is a graphical representation of the above table and depictsoxygen ingress in the nitrogen flushed pouches (Configurations A, C, Dand O). Configurations A, C, D and O were all prepared with an aluminumfoil top web. As the aluminum foil was very strong oxygen barrierproperties, the top web impact on oxygen ingress is negligible. Thus,the graph allows essentially a direct comparison between the bottom webbarrier properties.

At the beginning of the study (day=0) the oxygen levels in allconfigurations were about 0%, except for Configuration O with under 1%.Configuration A, comprised of the APET film without oxygen barrierproperties, allowed steady ingress of oxygen. At the end of the study(day=360), the oxygen level of Configuration A was at about 8%. Theother configurations C, D and O showed good barrier properties to oxygenpermeation. However, these configurations still allowed oxygen ingressto a certain extent as oxygen levels inside the pouches increased by thestudy endpoint (e.g., 2% for C, 1% for D).

Oxygen in Syringe Environments

FIG. 5 shows the oxygen levels in the filled syringes of ConfigurationsA, C and D. The filled syringes with degassed water had approximately 1%of residual oxygen at t0. According to FIG. 5, all the syringes' oxygenlevels are close to zero % of oxygen after 1 month. It is contemplatedthat because the pouch environments of Configurations A, C and D had alower oxygen levels than their syringes (See FIG. 4), the reduced oxygenlevel outside of the syringe promotes the egress of the residual oxygeninside the syringe as facilitated by the tip cap permeability accordingto Fick's law.

Nevertheless, a hysteresis phenomenon (lag effect) was observed betweenthe oxygen level in the pouch environment and the oxygen level insidethe syringe barrel. This is highlighted by the observation that afterone year, syringes in the C and D configurations (placed in EVOH film)remained at zero % oxygen levels while the oxygen levels increasedslightly in the respective pouches (2% for C, 1% for D). This effect wasmore prominent in configuration A, where the syringe in A (placed inregular APET film) remained at zero % oxygen for more than six months,after which the oxygen level started to increased after around theseventh month to 2% at the end of the study. In contrast, the oxygenlevel in the pouch environment of configuration A continually increasedto 8% at the end of the study. FIG. 6 depicts this hysteresis phenomenonof the oxygen levels between the pouch and in the syringe forconfiguration A alone.

It is contemplated that the hysteresis phenomenon may be attributed tothe oxygen sensor (OxyDot®) having intrinsic oxygen absorbing capacityas part of its sensing capability.

Example 3 Oxygen Levels in Packaging with Oxygen Absorbers Oxygen inPouch Environments

Configurations E, E bis, F and G were examined with respect to oxygenlevels inside the pouch and syringe environments. The study allowedcomparison with the different materials for the secondary packaging andoxygen absorber types. FIG. 7 shows the oxygen levels in the pouchenvironment at storage of 360 days at 25° C./60% RH. As described inExample 1, configurations E, E bis, F and G were sealed in ambient airenvironment at 21% oxygen. Offsets at t0 are attributed to the timebetween the sealing of the pouch and the oxygen level measurement. After2 to 3 days, the pouch environment of all the configurations (E, E bis,F and G) were at zero % oxygen. This indicates that the oxygen absorberabsorbs rapidly the initial oxygen content within the pouch. FIG. 8depicts in rapid absorption in more detail at in an 8-day scale graph.After 1 year, it was observed that configurations E and F are still atzero % of oxygen in the pouch environment (FIG. 7). For E bis, oxygenlevel started to increase after 6 months to a level of about 5% at the 1year endpoint. Pouch G comprised of an oxygen absorbing top web filmwith a capacity of around 12 cc of O₂. However, the oxygen level in thepouch environment in configuration G started to increase after one monthand the oxygen level was about 2% within the first 6 months, indicatingthat the oxygen absorbing capacity is not sufficient.

Regarding configurations E and F, the results indicate a ratio betweenthe film barrier property (oxygen transfer rate) and oxygen absorbercapacity can be manipulated to provide a zero % oxygen environment atthe end of the study. Thus, a secondary packaging with a poor barrier(APET) and a large O₂ absorber capacity (30 cc), i.e., configuration E,and a secondary packaging, with a good barrier (EVOH) and a small O₂absorber capacity (15 cc) can provide the same outcome (zero % pouchoxygen level).

Configuration E bis has the same secondary packaging materials but witha smaller capacity O₂ absorber (15 cc versus 30 cc for E). The resultsfrom FIG. 7 indicate that total capacity of the O₂ absorber was consumedat 6 months due to the poor barrier properties of the APET film. Oxygeningress is then equivalent to configuration A, i.e., intake of 5% oxygenwithin 6 months. The results also showed that configuration G with theoxygen absorber embedded in the polymer base film had the slowest oxygenremoval (3 days to zero % oxygen). Finally, the results showed that theoxygen absorption kinetics are very fast and can remove the total amountof oxygen in the pouch (approximately 6 to 7 cc of O2) in about 2 to 3days.

It was also observed, unexpectedly, that the secondary packaging airpressure in some of the configurations achieved a lower than atmosphericpressure and created a vacuum-like effect.

Oxygen in Syringe Environments

FIG. 9 depicts the oxygen levels of syringe environments inconfigurations E, F and G. The filled syringes with degassed water hadapproximately 1% of residual oxygen at t0. After 1 month, the oxygenlevels in the syringes of configurations E, F and G were at zero % ofoxygen. The results suggest that the system tends to equilibrium theoxygen level outside (zero %) and inside the syringe. Interestinglyhowever, the oxygen level in syringe G remains close to zero % oxygendespite the slight oxygen increase in the pouch (4% oxygen) after oneyear.

Example 4 Sealing Effects of Secondary Packaging Configurations andOxygen Levels

FIG. 10 illustrates a number of pouches from configurations E and G withdefective sealing. As described previously, all pouches with oxygenabsorbers were sealed at 21% oxygen level. The results from FIG. 10 showthat most of these samples reached zero % oxygen and went back up to 21%at different points of time, depending on the leak rate of each sampleor the rupture of the sealing cord after a certain time. Despite theover-sizing of the oxygen absorber (30 cc capacity in E compared to 7 ccof pure oxygen in the pouch volume), the oxygen level in the pouch canrise back to 21% very quickly if the package is leaking. The largenumber of defective pouches from configuration E suggests that somematerials have better sealing properties than others and is aconsideration for secondary packaging.

Example 5 Oxygen Levels of Syringes Filled in Ambient Conditions (˜21%O₂) in Blister Packaging with Oxygen Absorbers

This study assessed the oxygen level and extraction kinetic from asyringe filled in ambient conditions (concentration of O₂ is ˜21%).Three different blister configurations (n=10, per configuration)containing oxygen absorbers at a volume about 32 cc were prepared withthe following materials at ambient conditions (˜21% O₂):

Configu- Bottom Top Oxygen ration Web Web Absorber 1 (♦) PET/EVOH/PE500μm Paper/Alu9 μm/PE Sachet 30 cc 2 (▪) PET/EVOH/PET457 μm Paper/PET/Canister Alu20 μm 30 cc 3 (▴) PET/EVOH/LDPE457 μm Paper/Alu9 μm/PECanister 30 cc

1.25 mL glass syringes (Hypak™, Becton Dickinson & Co.) with an oxygenpermeable tip cap. were filled with purified water (not degassed) andsubsequently placed into one of the above blister packaging. Thus, thewater contained 8 ppm of initial oxygen levels (equilibrium with air at21% oxygen). An OxyDot® oxygen sensor (visual indicator of oxygenlevels) was stuck inside the syringe barrel before the filling. Oxygenlevels were assessed in the blister packaging and in the syringeaccording to the method described in Example 1.

Oxygen in Blister Environments

For all three configurations, the oxygen level is zero in the blisterpackaging after one day and remains at zero until the end of the study(360 days) (FIG. 11). This indicates that the kinetics of the oxygenabsorption has a much faster rate than the oxygen permeation flowthrough the blister. In FIG. 11, the oxygen concentration at T0 (timezero) should be 21% but the time delay between sample manufacturing andthe measurement (span of a few hours) is sufficient to get lowconcentrations on the first point of measurement.

Oxygen in Syringe Environments

For a syringe filled in ambient conditions (oxygen at 21%) and placed inthe blister packaging with oxygen absorber, the oxygen level in thesyringe decreases to 5% within six months, and less than 2% around oneyear for all three blister configurations (FIG. 12). The trend line inFIG. 12 appears to follow an exponential curve.

The study showed that the oxygen extraction flow from inside the syringeis a relatively slow process: it takes about six months to decrease theoxygen levels around 5%, and one year for oxygen levels around 2%. Thisslow kinetic indicates that syringes filled in ambient conditions willexpose the syringes' contents to about six months of oxygen exposure,thus likely having a high risk of oxidation/degradation. Although thepackaging eventually reduces the oxygen levels in the syringe to under2% in about a year, it is recommended to fill the syringe in inert(i.e., nitrogen) conditions to prevent possibility of degradation.

Example 6 Oxygen Levels in the Syringe at Various Fill and PackagingConditions

FIG. 13 summarizes oxygen levels in syringes of various fill andpackaging conditions over the course of a year. For a syringe filled ininert conditions (degassed, N₂ flushed) with ˜1% O₂ level and placed inambient air storage (no, secondary packaging), the oxygen levelseventually increased to 21% in approximately one year (▴). For a syringefilled in inert conditions (degassed, N₂ flushed) with ˜1% O₂ level andplaced in oxygen barrier packaging with an absorber, the oxygen levelsdecrease to zero in about one month and remain there after about oneyear (♦). A syringe filled in ambient conditions (O₂ level ˜21%) andplaced in oxygen barrier packaging with an absorber, the oxygen levelsdecrease to about 1% after one year (▪).

Example 7 Accelerated Stability Studies of a Morphine Formulation inPrimary and Secondary Packaging without Oxygen Absorber

2 mg/mL and 10 mg/mL morphine formulations were prepared according tothe following table.

Material 2 mg/mL 10 mg/mL Morphine sulfate pentahydrate 2.00 mg 10.00 mgSodium chloride 8.40 mg 7.50 mg Sodium citrate dihydrate 2.30 mg 3.45 mgCitric Acid monohydrate 0.74 mg 1.11 mg Disodium edetate dihydrate 0.111mg 0.111 mg Calcium chloride dihydrate 0.053 mg 0.053 mg Water forinjection s.q.f1 mL s.q.f1 mL

The 2 mg/mL and 10 mg/mL morphine formulations were evaluated under ICHaccelerated conditions at 40° C./75% RH for 6 months in 1.25 mL glasssyringes (Hypak™) with an oxygen permeable stopper. The syringescontaining the morphine formulations were placed in a secondary blisterpackaging of PET (polyethylene terephthalate) material with a paper lidbacking.

Results of the stability assay after 6 months storage at 40° C./75% RHrevealed that morphine content in stayed within specification parameters(NMT±10% change) for both concentrations. The assay values stayed stablein the 2 mg/mL formulation while the assay values for morphine decreasedslightly in the 10 mg/mL formulation but remained within specification.Similarly, total impurities level increased regularly over time but staybelow the specification (NMT 1.5%) for both strengths. pH values alsoremained stable over the 6 month storage period.

With respect to individual impurities, pseudomorphine appeared after 1month storage period and increased regularly over the storage period inboth the 2 mg/mL and 10 mg/mL morphine formulations. At the end of 6months storage, this impurity passed the specification limit (NMT 0.2%).The following table describes the pseudomorphine concentration over timein the 2 mg/mL morphine formulation:

2 mg/mL Morphine in Oxygen Barrier Packaging - Pseudomorphine Content T1T2 T3 T6 T0 Month Months Months Months Batch 1 0 0.05 0.05 0.1 0.21Batch 2 0 0.05 0.06 0.11 0.23 Batch 3 0 0.06 0.06 0.11 0.24

FIG. 14 depicts the presence of pseudomorphine over time in the 2 mg/mLformulation of three different batches. The pseudomorphine increase wasat a greater rate in the 10 mg/mL formulation and reached thespecification limit earlier (data not shown).

Example 8 Accelerated Stability Studies of a Morphine Formulation inPrimary and Secondary Packaging with Oxygen Absorber

In order to improve the stability and shelf life of the morphineformulation of Example 7, a secondary packaging with an oxygen absorberwas developed.

The alternative blister packaging included a thermoformed transparentshell made of a multilayer plastic film including PET and EVOH (Ethylenevinyl alcohol) (bottom web), and a heat sealed lidding material made ofpaper, PET and aluminum foil (top web). The EVOH layer of the bottom webpresents a very low permeability to oxygen molecules and the aluminumfoil is impermeable to any gas. Thus, this blister packaging restrictsthe atmospheric oxygen re-entry into the secondary packaging. An oxygenabsorber (30 cc capacity) was placed inside the blister. This absorberincluded an iron powder formula filled in a canister made of HDPEplastic and functioned to absorb any oxygen present in the secondarypackaging. The primary packaging container, i.e., syringe, containingthe morphine formulation was then placed in this alternative blisterpackaging.

Accelerated conditions at 40° C./75% RH for 6 months were assessedsimilarly to the previous example. For both strengths, the morphinecontent remained stable over time and the results were compliant withthe specification (90-110%). However, with the secondary packagingsystem with an oxygen absorber configuration, the impurity profile, andmore specifically the pseudomorphine impurity, was considerablyimproved. For all batches of the both strengths, the highest result oftotal impurities content were very low and stayed very far below thespecification limit (NMT 1.5%). The pseudomorphine content was very lowand even below the limit of quantification. Results of pseudomorphinecontent over the 6-month storage period in accelerated conditions arepresented in the following tables:

2 mg/mL Morphine in Oxygen Barrier Packaging - Pseudomorphine Content T1T2 T3 T6 T0 Month Months Months Months Batch 1 ND 0.05 0.03 0.04 0.04Batch 2 ND 0.05 0.03 0.04 0.03 Batch 3 ND 0.04 0.01 0.02 0.01

10 mg/mL Morphine in Oxygen Barrier Packaging - Pseudomorphine ContentT1 T2 T3 T6 T0 Month Months Months Months Batch 1 0.02 0.02 0.03 0.030.03 Batch 2 0.02 0.02 0.02 0.03 0.02 Batch 3 0.02 0.02 0.03 0.02 0.03

As shown above, the pseudomorphine content also stayed far below thespecification limit (NMT 0.2%). The data in the example showed that thestability results obtained on the batches packaged with the secondarypackaging system with an oxygen absorber show that the combination ofthe formulation with the buffer and chelating systems, the manufacturingprocess under nitrogen and the oxygen barrier packaging with an oxygenabsorber ensure a good preservation of the morphine formulation againstoxidation reactions.

Comparison of Morphine Formulations in Oxygen Barrier Packaging withStandard Packaging

In another study, the stability of 2 mg/mL morphine formulation wasexamined in standard packaging (i.e., without oxygen barrier secondarypackaging and/or oxygen absorber) and in oxygen barrier packaging (i.e.,with oxygen barrier secondary packaging and oxygen absorber) at ambient(25° C./60% RH) and accelerated conditions (40° C./75% RH). Thefollowing tables show that in both ambient and accelerated conditions,the pseudomorphine content in the morphine formulations with oxygenbarrier packaging was low and under the specification limits whereas themorphine formulations with standard packaging had unacceptable levels(0.2% or higher) of pseudomorphine:

2 mg/mL Morphine in Oxygen Barrier Packaging - Pseudomorphine ContentStorage - 25° C./60% RH T3 T6 T9 T12 T18 T24 T0 Months Months MonthsMonths Months Months Standard 0 0.040 0.060 0.080 0.110 0.210 0.300packaging O₂ 0 0.020 0.024 0.030 0.033 N/A 0.032 Barrier Packaging

2 mg/mL Morphine in Oxygen Barrier Packaging - Pseudomorphine ContentStorage - 40° C./75% RH T1 T2 T3 T6 T0 Month Months Months MonthsStandard 0.010 0.050 0.090 0.100 0.200 packaging O₂ 0.010 0.040 0.0200.030 0.030 Barrier Packaging

FIG. 15 is a graphical representation of the results in the previoustables. FIG. 15 (top) shows storage of 2 mg/mL morphine (MPH)formulations in standard and oxygen barrier packaging at ambientconditions (25° C./60% RH) for 24 months. The graph shows that the 2mg/mL morphine formulation in standard packaging, when stored at ambientconditions attained unacceptable pseudomorphine impurity levels ataround 18 months. FIG. 15 (bottom) storage of 2 mg/mL morphineformulations in standard and oxygen barrier packaging at acceleratedconditions (40° C./75% RH) for six months. At the end of the six monthperiod in accelerated conditions, the morphine formulations in standardpackaging reached the specification limit for pseudomorphine. Themorphine formulations in oxygen barrier packaging stored in both ambientand accelerated conditions were stable and had pseudomorphine levelswell below the specification limits.

Example 9 Stability Comparison of Morphine Formulations from Example 7in Oxygen Barrier Packaging with Marketed Morphine Formulation Productsof Equal Strengths

2 mg/mL, 5 mg/mL and 10 mg/mL morphine formulations were preparedaccording to Example 7 and filled into 1.25 mL glass syringes (Hypak™)with a stopper and placed into the secondary packaging system with anoxygen absorber as described in Example 8. The stability was comparedwith marketed morphine formulation products of equal strengths. Thetesting conditions and results are summarized in the following table:

Product Name Example 7 Example 7 Example 7 Morphine Morphine MorphineMorphine formulation Morphine formulation Morphine formulation Productwith O2 Product with O2 Product with O2 on barrier on barrier on barrierMarket packaging Market packaging Market packaging 2 mg/mL 2 mg/mL 5mg/mL 5 mg/mL 10 mg/mL 10 mg/mL Test time point & condition Tested at 2mos. Tested at Tested at After Tested at 6 mos. Tested at Tested at 6mos. 17 mos. 6 mos. at expiry at 13 mos. at Ambient 40° C./75% Ambient40° C./75% Ambient 40° C./75% conditions RH conditions RH conditions RHExpiry date 24 mos at 24 mos at 24 mos at Analytical 24 mos at 20°C.-25° C. 24 mos at 20° C.-25° C. 24 mos at 20° C.-25° C. Tests 20°C.-25° C. (proposed) 20° C.-25° C. (proposed) 20° C.-25° C. (proposed)Assay of 90%-110%  101%  101%  101%  100%  104%  100% Morphine (%) TotalNMT  1.7%  0.0%  0.7%  0.1%  1.1%  0.0% Impurities 1.0% (%) Codeine NMT0.06% 0.05% 0.06% 0.04% 0.07% 0.05% Impurity 0.2% Pseudo- NMT ND 0.04%0.23% 0.03% ND 0.03% morphine 0.2% impurity Oripavine NMT ND ND ND ND NDND impurity 0.2% 10- NMT 0.15% 0.04% 0.04% 0.06% 0.08% 0.03% hydroxy-0.2% morphine impurity Morphine-N- NMT ND ND ND 0.05% ND ND oxide 0.2%Normorphine NMT ND ND ND ND ND ND impurity 0.2% Morphinone NMT ND ND0.07% ND ND ND impurity 0.2% Apomorphine NMT ND — ND — ND ND impurity0.2% Unknown NMT RRT (%) RRT (%) RRT (%) RRT (%) RRT (%) RRT (%)impurity 0.2% 0.096 0.16 0.120 0.16 0.097 0.16 (0.38%) (0.02%) (0.21%)(0.03%) (0.10%) (0.02%) 0.144 1.102 0.144 (0.12%) (0.06%) (0.15%) 0.1650.166 (0.38%) (0.19%) 0.182 0.185 (0.08%) (0.10%) 0.213 0.284 (0.05%)(0.16%) 0.284 0.394 (0.15%) (0.22%) 0.391 (0.24%) 0.434 (0.08%)

As shown above, the morphine formulations of Example 7 in secondarypackaging system with an oxygen absorber had much better stability thanthe marketed morphine products of comparable strengths even when themarketed morphine products were stored at ambient conditions while themorphine formulations of Example 7 were stored in accelerated (40°C./75% RH) conditions. The stability assay shows that all of themarketed morphine products were out of specification limits for eithertotal and/or a particular impurity while the morphine formulations ofExample 7 were completely within specification. The marketed morphineproduct at 2 mg/mL presented a high level of total impurities (1.7%) andwas out of specification (according to ICH Q3B guidance) for two unknownimpurities; other unknown impurities were found significantly greaterthan 0.1%. The marketed morphine product at 5 mg/mL showed unacceptablepseudomorphine and unknown impurity levels. Finally, the marketedmorphine product at 10 mg/mL, analyzed at about half of its shelf lifehad a high total impurity level and up to 6 unknown impurities, 4 ofwhich being very close or that could be rounded to 0.2%; this indicatesthat this product is unlikely to meet stability acceptance criteriaafter two years. The results in this example demonstrate the increasedpurity and stability of exemplary morphine formulations described hereinwith the secondary packaging system with the oxygen absorber.

Example 10 Additional Stability Studies with Various Oxygen SensitiveDrugs in Standard and Oxygen Barrier Packaging

Additional stability studies were performed for hydromorphone andpromethazine formulation similar to the morphine standard vs. oxygenbarrier packaging study in Example 8.

Hydromorphone

The stability of 1 mg/mL and 10 mg/mL hydromorphone formulations wereexamined in standard packaging (i.e., without oxygen barrier secondarypackaging and/or oxygen absorber) and in oxygen barrier packaging (i.e.,with oxygen barrier secondary packaging and oxygen absorber) at ambient(25° C./60% RH) for 24 months and accelerated conditions (40° C./75% RH)for six months.

At ambient conditions, no significant difference in the impurity contentwas observed for the 1 mg/mL hydromorphone formulations in eitherstandard or oxygen barrier packaging. However, at acceleratedconditions, both 1 mg/mL and 10 mg/mL exhibit unknown impurity at RRT0.72 which exceeded or was close to the specification limits:

T1 T2 T3 T6 T0 Month Months Months Months 1 mg/mL Hydromorphone inOxygen Barrier Packaging - RRT 0.72 Impurity Content Storage - 40° C./75% RH Standard 0 N/A N/A 0.090 0.240 packaging O₂ 0 N/A N/A 0.0800.070 Barrier Packaging 10 mg/mL Hydromorphone in Oxygen BarrierPackaging - Pseudo morphine Content Storage - 40° C./75% RH Standard 0N/A N/A 0.080 0.190 packaging O₂ 0 N/A N/A 0.040 0.030 Barrier Packaging

FIG. 16 is a graphical representation of the results in the previoustable. FIG. 16 (top) shows storage of 1 mg/mL hydromorphone (HYD)formulations in standard and oxygen barrier packaging at acceleratedconditions (40° C./75% RH) for six months. The graph shows that the 1mg/mL hydromorphone formulation in standard packaging had anunacceptable unknown impurity (RRT 0.72) at the end of the six monthstorage period. FIG. 16 (bottom) storage of 10 mg/mL hydromorphoneformulations in standard and oxygen barrier packaging at acceleratedconditions (40° C./75% RH) for six months. At the end of the six monthperiod in accelerated conditions, the hydromorphone formulations instandard packaging was very close to the specification limit for theunknown impurity (RRT 0.72). The 1 mg/mL and 10 mg/mL hydromorphoneformulations in oxygen barrier packaging were stable with impuritylevels stable and below the specification limits.

Promethazine

The stability of 25 mg/mL promethazine formulations were examined instandard packaging (i.e., without oxygen barrier secondary packagingand/or oxygen absorber) and in oxygen barrier packaging (i.e., withoxygen barrier secondary packaging and oxygen absorber) at ambient (25°C./60% RH) for 24 months and accelerated conditions (40° C./75% RH) forsix months.

The following tables show that in both ambient and acceleratedconditions, the sulfoxide impurity content in the promethazineformulations with oxygen barrier packaging were under the specificationlimits whereas the promethazine formulations with standard packagingquickly had unacceptable levels (0.2% or higher) of the sulfoxideimpurity:

25 mg/mL Promethazine in Oxygen Barrier Packaging - Sulfoxide ContentStorage - 25° C./60% RH T0 T3 Months T6 Months T9 Months T12 Months T18Months T24 Months Standard 0.17 0.67 1.21 N/A 1.55 0.21 0.30 packagingO₂ Barrier 0.12 0.17 0.17 N/A 0.13 N/A 0.032 Packaging

25 mg/mL Promethazine in Oxygen Barrier Packaging - Sulfoxide ContentStorage - 40° C./75% RH T0 T1 Month T2 Months T3 Months T6 MonthsStandard 0.173 0.451 N/A 0.854 1.46 packaging O₂ Barrier 0.12 0.1770.114 0.104 0.12 Packaging

FIG. 17 is a graphical representation of the results in the previoustable. FIG. 17 (top) shows storage of 25 mg/mL promethazine (PRZ)formulations in standard and oxygen barrier packaging at ambientconditions (25° C./60% RH) for twelve months. The graph shows that thepromethazine formulation in standard packaging had an unacceptablelevels of sulfoxide by the three-month assay point which continued toincrease to the end of the storage period. The promethazine formulationin oxygen barrier packaging had sulfoxide impurity levels under thespecification limits. FIG. 17 (bottom) storage of 25 mg/mL promethazineformulations in standard and oxygen barrier packaging at acceleratedconditions (40° C./75% RH) for six months. At the one-month assay point,the promethazine formulations in standard packaging already exceeded thespecification limit for sulfoxide. The promethazine formulations inoxygen barrier packaging were stable with sulfoxide impurity levelsstable and below the specification limits.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

What is claimed is:
 1. A pharmaceutical packaging system for aninjectable oxygen-sensitive drug, the packaging system comprising: (i) asyringe filled under inert conditions with an injectableoxygen-sensitive drug, wherein the syringe has an oxygen permeable tipcap and wherein the oxygen-sensitive drug is one of morphine,hydromorphone, and promethazine; (ii) a hermetically sealed oxygenbarrier blister packaging which houses the syringe, wherein the blisterpackaging comprises a multilayer bottom web comprising ethylene vinylalcohol (EVOH) and a multilayer top web lid comprising aluminum foil orEVOH; and (iii) an oxygen absorber, wherein the oxygen absorber reducesthe oxygen level present from the time of packaging assembly to aboutzero percent in about one to three days in the blister packaging and inabout one to three months in the syringe.
 2. The pharmaceuticalpackaging system of claim 1, wherein the syringe is plastic or glass. 3.The pharmaceutical packaging system of claim 1, wherein the blisterpackaging is an aluminum-based cold formed blister, or a molded blister.4. The pharmaceutical packaging system of claim 1, wherein the oxygenabsorber is placed inside the blister packaging.
 5. The pharmaceuticalpackaging system of claim 1, wherein the oxygen absorber is a canister.6. The pharmaceutical packaging system of claim 1, wherein the oxygenabsorber has a capacity to absorb about 30 cc oxygen at 1 atm.
 7. Thepharmaceutical packaging system of claim 1, wherein the oxygen absorberis iron-based.
 8. The pharmaceutical packaging system of claim 1,wherein the oxygen absorber reduces the oxygen level in the blisterpackaging from the time of packaging assembly to about zero percent atabout one day.
 9. The pharmaceutical packaging system of claim 1,wherein the oxygen absorber reduces the oxygen level in the syringe fromthe time of packaging assembly to about zero percent at about one month.10. The pharmaceutical packaging system of claim 1, wherein the oxygenlevel remains at about zero percent in the syringe and the blisterpackaging for at least three years.
 11. The pharmaceutical packagingsystem of claim 1, wherein the injectable oxygen-sensitive drug ismorphine.
 12. The pharmaceutical packaging system of claim 1, whereinthe injectable oxygen-sensitive drug is hydromorphone.
 13. Thepharmaceutical packaging system of claim 1, wherein the injectableoxygen-sensitive drug is promethazine.
 14. The pharmaceutical packagingsystem of claim 1, wherein the blister packaging is a thermoformedblister.
 15. A pharmaceutical packaging system for injectable morphine,the packaging system comprising: (i) a syringe filled under inertconditions with morphine, wherein the syringe has an oxygen permeabletip cap, (ii) a hermetically sealed oxygen barrier blister packagingwhich houses the syringe, wherein the blister packaging comprises amultilayer bottom web comprising ethylene vinyl alcohol (EVOH) and amultilayer top web lid comprising aluminum foil or EVOH; and (iii) anoxygen absorber, wherein the oxygen absorber reduces the oxygen levelfrom the time of packaging assembly to about zero percent in about oneto three days in the blister packaging and in about one to three monthsin the syringe.
 16. A pharmaceutical packaging system for injectablehydromorphone, the packaging system comprising: (i) a syringe filledunder inert conditions with hydromorphone, wherein the syringe has anoxygen permeable tip cap, (ii) a hermetically sealed oxygen barrierblister packaging which houses the syringe, wherein the blisterpackaging comprises a multilayer bottom web comprising ethylene vinylalcohol (EVOH) and a multilayer top web lid comprising aluminum foil orEVOH; and (iii) an oxygen absorber, wherein the oxygen absorber reducesthe oxygen level from the time of packaging assembly to about zeropercent in about one to three days in the blister packaging and in aboutone to three months in the syringe.
 17. A pharmaceutical packagingsystem for injectable promethazine, the packaging system comprising: (i)a syringe filled under inert conditions with promethazine, wherein thesyringe has an oxygen permeable tip cap, (ii) a hermetically sealedoxygen barrier blister packaging which houses the syringe, wherein theblister packaging comprises a multilayer bottom web comprising ethylenevinyl alcohol (EVOH) and a multilayer top web lid comprising aluminumfoil or EVOH; and (iii) an oxygen absorber, wherein the oxygen absorberreduces the oxygen level from the time of packaging assembly to aboutzero percent in about one to three days in the blister packaging and inabout one to three months in the syringe.